Pathogen-inspired drug delivery to the central nervous system

Tissue Barriers

Volumn 2, Issue 4, 2014, Pages

  McCall, Rebecca L ^a   Cacaccio, Joseph ^b   Wrabel, Eileen ^c   Schwartz, Mary E ^c   Coleman, Timothy P ^b,c,d,e   Sirianni, Rachael W ^a  

^a BARROW NEUROLOGICAL INSTITUTE   (United States)

^b Blue Ocean Biomanufacturing Inc   (United States)

^c Nemucore Medical Innovations Inc   (United States)

^d NORTHEASTERN UNIVERSITY   (United States)

^e Foundation for the Advancement of Personalized Medicine Manufacturing   (United States)

Author keywords

Brain; Central nervous system; Drug delivery; Pathogen; Peptide; Toxin

Indexed keywords

ALPHA BUNGAROTOXIN; ALPHA ELAPITOXIN AI2A; CHLOROTOXIN; COBROTOXIN; CONANTOKIN G; CONOPEPTIDE; DENDROTOXIN; GELATINASE A; GLYCOPROTEIN; HANNAH TOXIN; LAMININ RECEPTOR; MATRIX PROTEIN; NANOCARRIER; NANOPARTICLE; NERVE CELL ADHESION MOLECULE; NEUROTROPHIC FACTOR; OMEGA CONOTOXIN MVIIA; PEPTIDE KC2S; QUANTUM DOT; RABIES VIRUS GLYCOPROTEIN; RECOMBINANT PROTEIN; SCORPION VENOM; SILICA NANOPARTICLE; SNAIL VENOM; SNAKE VENOM; TETANUS TOXIN; TM 601; UNCLASSIFIED DRUG;

AMYOTROPHIC LATERAL SCLEROSIS; BLOOD BRAIN BARRIER; BORRELIA; BRAIN TUMOR; CENTRAL NERVOUS SYSTEM; CLOSTRIDIUM BOTULINUM; CLOSTRIDIUM TETANI; DRUG DELIVERY SYSTEM; ESCHERICHIA COLI; GLIOMA; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; JAPANESE ENCEPHALITIS VIRUS; LISTERIA; NONHUMAN; PATHOGENICITY; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN ENGINEERING; RABIES VIRUS; REVIEW; SINDBIS VIRUS; TICK BORNE ENCEPHALITIS VIRUS; WEST NILE VIRUS;

EID: 84962209087     PISSN: 21688362     EISSN: 21688370     Source Type: Journal    
DOI: 10.4161/21688362.2014.944449     Document Type: Review

References (155)

1. Friden PM, Walus LR, Musso GF, Taylor MA, Malfroy B, Starzyk RM. Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier. Proc Natl Acad Sci 1991; 88:4771-5.
2. Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2005; 2:3-14; PMID:15717053; http://dx.doi.org/10.1602/neurorx.2.1.3.
3. Bencurova E, Mlynarcik P, Bhide M. An insight into the ligand-receptor interactions involved in the translocation of pathogens across blood-brain barrier. FEMS Immunol Med Microbiol 2011; 63:297-318; PMID:22092557; http://dx.doi.org/10.1111/j.1574-695X.2011.00867.x
4. Kim KS. Mechanisms of microbial traversal of the blood-brain barrier. Nat Rev Microbiol 2008; 6:625-34; PMID:18604221.
5. Salinas S, Schiavo G, Kremer EJ. A hitchhiker’s guide to the nervous system: the complex journey of viruses and toxins. Nat Rev Microbiol 2010; 8:645-55; PMID:20706281; http://dx.doi.org/10.1038/nrmicro2395.
6. Donaldson EF, Lindesmith LC, Lobue AD, Baric RS. Viral shape-shifting: norovirus evasion of the human immune system. Nat Rev Microbiol 2010; 8:231-41; PMID:20125087; http://dx.doi.org/10.1038/nrmicro2296.
7. Moody MF. Geometry of phage head construction. J Mol Biol 1999; 293:401-33; PMID: 10529353.
8. Morton VL, Stockley PG, Stonehouse NJ, Ashcroft AE. Insights into virus capsid assembly from noncovalent mass spectrometry. Mass Spectrom Rev 2008; 27:575-95; PMID:18498137; http://dx.doi.org/10.1002/mas.20176.
9. Jolly CL, Sattentau QJ. Attachment factors. Adv Exp Med Biol 2013; 790:1-23; PMID:23884583; http://dx.doi.org/10.1007/978-1-4614-7651-1_1.
10. Mateu MG. Assembly, stability and dynamics of virus capsids. Arch Biochem Biophys 2013; 531:65-79; PMID:23142681.
11. Dokland T. Freedom and restraint: themes in virus capsid assembly. Structure 2000; 8:R157-62; PMID:10997898; http://dx.doi.org/10.1016/S0969- 2126(00)00181-7.
12. Wu E, Nemerow GR. Virus yoga: the role of flexibility in virus host cell recognition. Trends Microbiol 2004; 12:162-9; PMID:15051066; http://dx.doi.org/10.1016/j.tim.2004.02.005.
13. Hasegawa K, Hu C, Nakamura T, Marks JD, Russell SJ, Peng KW. Affinity thresholds for membrane fusion triggering by viral glycoproteins. J Virol 2007; 81:13149-57; PMID:17804513; http://dx.doi.org/10.1128/JVI.01415-07.
14. McGavern DB, Kang SS. Illuminating viral infections in the nervous system. Nat Rev Immunol 2011; 11:318-29; PMID:21508982; http://dx.doi.org/10.1038/nri2971.
15. Johnson N, Phillpotts R, Fooks AR. Airborne transmission of lyssaviruses. J Med Microbiol 2006; 55:785-90; PMID:16687600; http://dx.doi.org/10.1099/jmm.0.46370-0.
16. Lafon M. Rabies virus receptors. J Neurovirol 2005; 11:82-7.
17. Langevin C, Jaaro H, Bressanelli S, Fainzilber M, Tuffereau C. Rabies virus glycoprotein (RVG) is a trimeric ligand for the N-terminal cysteine-rich domain of the mammalian p75 neurotrophin receptor. J Biol Chem 2002; 277:37655-62; PMID:12163480; http://dx.doi.org/10.1074/jbc.M201374200.
18. Thoulouze MI, Lafage M, Schachner M, Hartmann U, Cremer H, Lafon M. The neural cell adhesion molecule is a receptor for rabies virus. J Virol 1998; 72:7181-90; PMID:9696812.
19. Lentz TL. Rabies virus binding to an acetylcholine receptor alpha-subunit peptide. J Mol Recognit 1990; 3:82-8.
20. Superti F, Derer M, Tsiang H. Mechanism of rabies virus entry into CER cells. J Gen Virol 1984; 65(Pt 4):781-9; PMID:6423770; http://dx.doi.org/10.1099/0022-1317-65-4-781.
21. Ivey NS, MacLean AG, Lackner AA. Acquired immunodeficiency syndrome and the blood-brain barrier. J Neurovirol 2009; 15:111-22; PMID:19306229; http://dx.doi.org/10.1080/13550280902769764.
22. Strazza M, Pirrone V, Wigdahl B, Nonnemacher MR. Breaking down the barrier: the effects of HIV- 1 on the blood-brain barrier. Brain Res 2011; 1399:96-115; PMID:21641584;http://dx.doi.org/10.1016/j.brainres.2011.05.015.
23. King JE, Eugenin EA, Buckner CM, Berman JW. HIV tat and neurotoxicity. Microbes Infect 2006; 8:1347-57; PMID:16697675; http://dx.doi.org/10.1016/j.micinf.2005.11.014.
24. Cohen SS, Li C, Ding L, Cao Y, Pardee AB, Shevach EM, Cohen DI. Pronounced acute immunosuppression in vivo mediated by HIV Tat challenge. Proc Natl Acad Sci U S A 1999; 96:10842-7; PMID:10485913; http://dx.doi.org/10.1073/pnas.96.19.10842.
25. Banks WA, Robinson SM, Nath A. Permeability of the blood-brain barrier to HIV-1 Tat. Exp Neurol 2005; 193:218-27; PMID:15817280; http://dx.doi.org/10.1016/j.expneurol.2004.11.019.
26. Qin Y, Zhang Q, Chen H, Yuan W, Kuai R, Xie F, Zhang L, Wang X, Zhang Z, Liu J, et al. Comparison of four different peptides to enhance accumulation of liposomes into the brain. J Drug Target 2012; 20:235-45; PMID:22188312; http://dx.doi.org/10.3109/1061186X.2011.639022.
27. Rusnati M, Presta M. HIV-1 Tat protein and endothelium: from protein/cell interaction to AIDSassociated pathologies. Angiogenesis 2002; 5:141-51; PMID:12831055; http://dx.doi.org/10.1023/A:1023892223074.
28. Margolin W. Sculpting the bacterial cell. Curr Biol 2009; 19:R812-22; PMID:19906583.
29. Typas A, Banzhaf M, Gross CA, Vollmer W. From the regulation of peptidoglycan synthesis to bacterial growth and morphology. Nat Rev Microbiol 2012; 10:123-36;
30. Huang SH, Jong AY. Cellular mechanisms of microbial proteins contributing to invasion of the blood-brain barrier. Cell Microbiol 2001; 3:277-87; PMID:11298651; http://dx.doi.org/10.1046/j.1462-5822.2001.00116.x
31. Toivonen JM, Olivan S, Osta R. Tetanus toxin C-fragment: the courier and the cure? Toxins 2010; 2:2622-44; PMID:22069568; http://dx.doi.org/10.3390/toxins2112622.
32. Rossetto O, Scorzeto M, Megighian A, Montecucco C. Tetanus neurotoxin. Toxicon: Off J Int Soc Toxinol 2013; 66:59-63; PMID:23419592; http://dx.doi.org/10.1016/j.toxicon.2012.12.027.
33. Matsuda M, Lei DL, Sugimoto N, Ozutsumi K, Okabe T. Isolation, purification, and characterization of fragment B, the NH2-terminal half of the heavy chain of tetanus toxin. Infect Immun 1989; 57:3588-93; PMID:2478476.
34. Boquet P, Duflot E. Tetanus toxin fragment forms channels in lipid vesicles at low pH. Proc Natl Acad Sci U S A 1982; 79:7614-8; PMID:6296842; http://dx.doi.org/10.1073/pnas.79.24.7614.
35. Centers for Disease Control and Prevention. Adult vaccination coverage–United States, 2010. MMWR Morbidity and mortality weekly report 2012; 61:66-72.
36. Akaike N, Shin MC, Wakita M, Torii Y, Harakawa T, Ginnaga A, Kato K, Kaji R, Kozaki S. Transsynaptic inhibition of spinal transmission by A2 botulinum toxin. J Physiol 2013; 591:1031-43; PMID:23109108; http://dx.doi.org/10.1113/jphysiol.2012.242131.
37. Antonucci F, Rossi C, Gianfranceschi L, Rossetto O, Caleo M. Long-distance retrograde effects of botulinum neurotoxin A. J Neurosci: Off J Soc Neurosci 2008; 28:3689-96; PMID:18385327; http://dx.doi.org/10.1523/JNEUROSCI.0375-08.2008.
38. Pulzova L, Bhide M. Outer surface proteins of Borrelia: peerless immune evasion tools. Curr Protein Pept Sci 2014; 15:75-88; PMID:24555888; http://dx.doi.org/10.2174/1389203715666140221124213.
39. Leong JM, Wang H, Magoun L, Field JA, Morrissey PE, Robbins D, Tatro JB, Coburn J, Parveen N. Different classes of proteoglycans contribute to the attachment of Borrelia burgdorferi to cultured endothelial and brain cells. Infect Immun 1998; 66:994-9; PMID:9488387.
40. Moriarty TJ, Shi M, Lin YP, Ebady R, Zhou H, Odisho T, Hardy PO, Salman-Dilgimen A, Wu J, Weening EH, et al. Vascular binding of a pathogen under shear force through mechanistically distinct sequential interactions with host macromolecules. Mol Microbiol 2012; 86:1116-31; PMID:23095033; http://dx.doi.org/10.1111/mmi.12045.
41. Pulzova L, Kovac A, Mucha R, Mlynarcik P, Bencurova E, Madar M, Novak M, Bhide M. OspA-CD40 dyad: ligand-receptor interaction in the translocation of neuroinvasive Borrelia across the blood-brain barrier. Sci Rep 2011; 1:86; PMID:22355605; http://dx.doi.org/10.1038/srep00086.
42. ReddyMA, PrasadaraoNV,Wass CA, KimKS. Phosphatidylinositol 3-kinase activation and interaction with focal adhesion kinase in Escherichia coli K1 invasion of human brain microvascular endothelial cells. J Biol Chem 2000; 275:36769-74; PMID:10973983; http://dx.doi.org/10.1074/jbc.M007382200.
43. Schmidt G, Sehr P, Wilm M, Selzer J, Mann M, Aktories K. Gln 63 of Rho is deamidated by Escherichia coli cytotoxic necrotizing factor-1. Nature 1997; 387:725-9; PMID:9192900; http://dx.doi.org/10.1038/42735.
44. Khan NA, Shin S, Chung JW, Kim KJ, Elliott S, Wang Y, Kim KS. Outer membrane protein A and cytotoxic necrotizing factor-1 use diverse signaling mechanisms for Escherichia coli K1 invasion of human brain microvascular endothelial cells. Microb Pathogenesis 2003; 35:35-42; PMID:12860457; http://dx.doi.org/10.1016/S0882-4010(03)00090-1.
45. Abouseada NM, Assafi MS, Mahdavi J, Oldfield NJ, Wheldon LM, Wooldridge KG, Ala’Aldeen DA. Mapping the laminin receptor binding domains of Neisseria meningitidis PorA and Haemophilus influenzae OmpP2. PloS One 2012; 7: e46233; PMID:23049988.
46. Kim KJ, Chung JW, Kim KS. 67-kDa laminin receptor promotes internalization of cytotoxic necrotizing factor 1-expressing Escherichia coli K1 into human brain microvascular endothelial cells. J Biol Chem 2005; 280:1360-8; PMID:15516338; http://dx.doi.org/10.1074/jbc.M410176200.
47. Orihuela CJ, Mahdavi J, Thornton J, Mann B, Wooldridge KG, Abouseada N, Oldfield NJ, Self T, Ala’Aldeen DA, Tuomanen EI. Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models. J Clin Investi 2009; 119:1638-46; PMID:19436113; http://dx.doi.org/10.1172/JCI36759.
48. Ransohoff RM, Kivisakk P, Kidd G. Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 2003; 3:569-81; PMID:12876559; http://dx.doi.org/10.1038/nri1130.
49. Drevets DA, Dillon MJ, Schawang JS, Van Rooijen N, Ehrchen J, Sunderkotter C, Leenen PJ. The Ly-6Chigh monocyte subpopulation transports Listeria monocytogenes into the brain during systemic infection of mice. J Immunol 2004; 172:4418-24; http://dx.doi.org/10.4049/jimmunol.172.7.4418.
50. Hertzig T, Weber M, Greiffenberg L, Holthausen BS, Goebel W, Kim KS, Kuhn M. Antibodies present in normal human serum inhibit invasion of human brain microvascular endothelial cells by Listeria monocytogenes. Infect Immun 2003; 71:95-100; PMID:12496153; http://dx.doi.org/10.1128/IAI.71.1.95-100.2003.
51. Remuzgo-Martinez S, Pilares-Ortega L, Icardo JM, Valdizan EM, Vargas VI, Pazos A, Ramos-Vivas J. Microglial activation and expression of immunerelated genes in a rat ex vivo nervous system model after infection with Listeria monocytogenes. Glia 2013; 61:611-22; PMID:23322603; http://dx.doi.org/10.1002/glia.22459.
52. Greiffenberg L, Goebel W, Kim KS, Weiglein I, Bubert A, Engelbrecht F, Stins M, Kuhn M. Interaction of Listeria monocytogenes with human brain microvascular endothelial cells: InlB-dependent invasion, long-term intracellular growth, and spread from macrophages to endothelial cells. Infect Immun 1998; 66:5260-7; PMID:9784531.
53. Klint JK, Senff S, Rupasinghe DB, Er SY, Herzig V, Nicholson GM, King GF. Spider-venom peptides that target voltage-gated sodium channels: pharmacological tools and potential therapeutic leads. Toxicon: Off J Int Soc Toxinol 2012; 60:478-91; PMID:22543187; http://dx.doi.org/10.1016/j. toxicon.2012.04.337.
54. King GF. Venoms as a platform for human drugs: translating toxins into therapeutics. Expert Opin Biol Ther 2011; 11:1469-84; PMID:21939428; http://dx.doi.org/10.1517/14712598.2011.621940.
55. Norton RS, Pallaghy PK. The cystine knot structure of ion channel toxins and related polypeptides. Toxicon: Off J Int Soc Toxinol 1998; 36:1573-83; PMID:9792173; http://dx.doi.org/10.1016/S0041- 0101(98)00149-4.
56. Mouhat S, Jouirou B, Mosbah A, De Waard M, Sabatier JM. Diversity of folds in animal toxins acting on ion channels. Biochem J 2004; 378:717-26; PMID:14674883; http://dx.doi.org/10.1042/BJ20031860.
57. Takahashi H, Kim JI, Min HJ, Sato K, Swartz KJ, Shimada I. Solution structure of hanatoxin1, a gating modifier of voltage-dependent K(C) channels: common surface features of gating modifier toxins. J Mol Biol 2000; 297:771-80; PMID:10731427; http://dx.doi.org/10.1006/jmbi.2000.3609.
58. Chagot B, Escoubas P, Villegas E, Bernard C, Ferrat G, Corzo G, Lazdunski M, Darbon H. Solution structure of Phrixotoxin 1, a specific peptide inhibitor of Kv4 potassium channels from the venom of the theraphosid spider Phrixotrichus auratus. Protein Sci 2004; 13:1197-208; PMID:15096626; http://dx.doi.org/10.1110/ps.03584304.
59. Raposo C, Odorissi PA, Oliveira AL, Aoyama H, Ferreira CV, Verinaud L, Fontana K, Ruela-de- Sousa RR, da Cruz-Hofling MA. Effect of Phoneutria nigriventer venom on the expression of junctional protein and P-gp efflux pump function in the blood-brain barrier. Neurochem Res 2012; 37:1967-81; PMID:22684283; http://dx.doi.org/10.1007/s11064-012-0817-y
60. de Paula Le Sueur L, Kalapothakis E, da Cruz- Hofling MA. Breakdown of the blood-brain barrier and neuropathological changes induced by Phoneutria nigriventer spider venom. Acta Neuropathol 2003; 105:125-34; PMID:12536223.
61. Gotti C, Zoli M, Clementi F. Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Trends Pharmacol Sci 2006; 27:482-91; PMID:16876883; http://dx.doi.org/10.1016/j.tips.2006.07.004.
62. Harvey AL. Snake venom peptides. Handbook of Biologically Active Peptides 2006:355-62.
63. Kini RM, Doley R. Structure, function and evolution of three-finger toxins: mini proteins with multiple targets. Toxicon: Off J Int Soc Toxinol 2010; 56:855-67; PMID:20670641; http://dx.doi.org/10.1016/j.toxicon.2010.07.010.
64. Kumari S, Borroni V, Chaudhry A, Chanda B, Massol R, Mayor S, Barrantes FJ. Nicotinic acetylcholine receptor is internalized via a Rac-dependent, dynamin-independent endocytic pathway. J Cell Biol 2008; 181:1179-93; PMID:18591431; http://dx.doi.org/10.1083/jcb.200709086.
65. Osipov AV, Rucktooa P, Kasheverov IE, Filkin SY, Starkov VG, Andreeva TV, Sixma TK, Bertrand D, Utkin YN, Tsetlin VI. Dimeric alpha-Cobratoxin X-ray Structure: Localization of intermolecular disulfides and possible mode of binding to nicotinic acetylcholine receptors*. J Biol Chem 2012; 287:6725-34; PMID:22223648; http://dx.doi.org/10.1074/jbc.M111.322313.
66. Alama A, Bruzzo C, Cavalieri Z, Forlani A, Utkin Y, Casciano I, Romani M. Inhibition of the nicotinic acetylcholine receptors by cobra venom alphaneurotoxins: is there a perspective in lung cancer treatment? PloS One 2011; 6:e20695; PMID: 21695184.
67. Lesovoy DM, Bocharov EV, Lyukmanova EN, Kosinsky YA, Shulepko MA, Dolgikh DA, Kirpichnikov MP, Efremov RG, Arseniev AS. Specific membrane binding of neurotoxin II can facilitate its delivery to acetylcholine receptor. Biophys J 2009; 97:2089-97; PMID:19804741; http://dx.doi.org/10.1016/j.bpj.2009.07.037.
68. Colquhoun D, Unwin N, Shelley C, Hatton C, Sivilotti L. Burger’s medicinal chemistry and drug discovery. New York: Wiley-Interscience; 2003.
69. Redwan el RM. Animal-derived pharmaceutical proteins. J Immunoassay Immunochem 2009; 30:262-90; PMID:19591041; http://dx.doi.org/10.1080/15321810903084400.
70. Essack M, Bajic VB, Archer JA. Conotoxins that confer therapeutic possibilities. Marine drugs 2012; 10:1244-65; PMID:22822370; http://dx.doi.org/10.3390/md10061244.
71. Lewis RJ, Dutertre S, Vetter I, Christie MJ. Conus venom peptide pharmacology. Pharmacol Rev 2012; 64:259-98; PMID:22407615; http://dx.doi.org/10.1124/pr.111.005322.
72. Hone AJ, Ruiz M, Scadden M, Christensen S, Gajewiak J, Azam L, McIntosh JM. Positional scanning mutagenesis of alpha-conotoxin PeIA identifies critical residues that confer potency and selectivity for alpha6/alpha3beta2beta3 and alpha3beta2 nicotinic acetylcholine receptors. J Biol Chem 2013; 288:25428-39; PMID:23846688; http://dx.doi.org/10.1074/jbc.M113.482059.
73. National Select Agent Registry. Centers for Disease Control; 2013; http://www.selectagents.gov/Select %20Agents%20and%20Toxins%20List.html
74. Ding J, Chua PJ, Bay BH, Gopalakrishnakone P. Scorpion venoms as a potential source of novel cancer therapeutic compounds. Exp Biol Med (Maywood) 2014; 239(4):387-93.
75. Lyons SA, O’Neal J, Sontheimer H. Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin. Glia 2002; 39:162-73; PMID:12112367; http://dx.doi.org/10.1002/glia.10083.
76. Gordon D, Gurevitz M. The selectivity of scorpion alpha-toxins for sodium channel subtypes is determined by subtle variations at the interacting surface. Toxicon: Off J Int Soc Toxinol 2003; 41:125-8; PMID:12565730; http://dx.doi.org/10.1016/S0041-0101(02)00294-5.
77. Zhijian C, Feng L, Yingliang W, Xin M, Wenxin L. Genetic mechanisms of scorpion venom peptide diversification. Toxicon 2006; 47:348-55; PMID:16387337; http://dx.doi.org/10.1016/j. toxicon.2005.11.013.
78. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJA. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011; 29:341-5; PMID:21423189; http://dx.doi.org/10.1038/nbt.1807.
79. Kumar P, Wu H, McBride JL, Jung KE, Kim MH, Davidson BL, Lee SK, Shankar P, Manjunath N. Transvascular delivery of small interfering RNA to the central nervous system. Nature 2007; 448:39-43; PMID:17572664; http://dx.doi.org/10.1038/nature05901.
80. Soroceanu L, Gillespie Y, Khazaeli MB, Sontheimer H. Use of chlorotoxin for targeting of primary brain tumors. Cancer Res 1998; 58:4871-9; PMID:9809993.
81. Veiseh M, Gabikian P, Bahrami SB, Veiseh O, Zhang M, Hackman RC, Ravanpay AC, Stroud MR, Kusuma Y, Hansen SJ, et al. Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci. Cancer Res 2007; 67:6882-8; PMID:17638899; http://dx.doi.org/10.1158/0008-5472.CAN-06-3948.
82. Mamelak AN, Rosenfeld S, Bucholz R, Raubitschek A, Nabors LB, Fiveash JB, Shen S, Khazaeli MB, Colcher D, Liu A, et al. Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma. J Clin Oncol 2006; 24:3644-50; PMID:16877732; http://dx.doi.org/10.1200/JCO.2005.05.4569.
83. Costa PM, Cardoso AL, Mendonca LS, Serani A, Custodia C, Conceicao M, Simoes S, Moreira JN, Pereira de Almeida L, Pedroso de Lima MC. Tumor-targeted chlorotoxin-coupled nanoparticles for nucleic acid delivery to glioblastoma cells: a promising system for glioblastoma treatment. Mol Ther Nucleic Acids 2013; 2:e100; PMID:23778499.
84. Huang R, Ke W, Han L, Li J, Liu S, Jiang C. Targeted delivery of chlorotoxin-modified DNAloaded nanoparticles to glioma via intravenous administration. Biomaterials 2011; 32:2399-406; PMID:21185076; http://dx.doi.org/10.1016/j. biomaterials.2010.11.079.
85. Kievit FM, Veiseh O, Fang C, Bhattarai N, Lee D, Ellenbogen RG, Zhang M. Chlorotoxin labeled magnetic nanovectors for targeted gene delivery to glioma. ACS Nano 2010; 4:4587-94; PMID:20731441; http://dx.doi.org/10.1021/nn1008512.
86. Mok H, Veiseh O, Fang C, Kievit FM, Wang FY, Park JO, Zhang M. pH-Sensitive siRNA nanovector for targeted gene silencing and cytotoxic effect in cancer cells. Mol Pharm 2010; 7:1930-9; PMID:20722417; http://dx.doi.org/10.1021/mp100221h
87. Veiseh O, Kievit FM, Fang C, Mu N, Jana S, Leung MC, Mok H, Ellenbogen RG, Park JO, Zhang M. Chlorotoxin bound magnetic nanovector tailored for cancer cell targeting, imaging, and siRNA delivery. Biomaterials 2010; 31:8032-42; PMID:20673683; http://dx.doi.org/10.1016/j. biomaterials.2010.07.016.
88. Veiseh O, Kievit FM, Gunn JW, Ratner BD, Zhang M. A ligand-mediated nanovector for targeted gene delivery and transfection in cancer cells. Biomaterials 2009; 30:649-57; PMID:18990439; http://dx.doi.org/10.1016/j.biomaterials.2008.10.003.
89. Kasai T, Nakamura K, Vaidyanath A, Chen L, Sekhar S, El-Ghlban S, Okada M, Mizutani A, Kudoh T, Murakami H, et al. Chlorotoxin fused to IgG-Fc inhibits glioblastoma cell motility via receptor-mediated endocytosis. J Drug Del 2012; 2012:975763; PMID:23304519; http://dx.doi.org/10.1155/2012/975763.
90. Locatelli E, Naddaka M, Uboldi C, Loudos G, Fragogeorgi E, Molinari V, Pucci A, Tsotakos T, Psimadas D, Ponti J, et al. Targeted delivery of silver nanoparticles and alisertib: in vitro and in vivo synergistic effect against glioblastoma. Nanomedicine 2014; 9(6):839-49; PMID:24433240.
91. Locatelli E, Broggi F, Ponti J, Marmorato P, Franchini F, Lena S, Franchini MC. Lipophilic silver nanoparticles and their polymeric entrapment into targeted-PEG-based micelles for the treatment of glioblastoma. Adv Healthc Mater 2012; 1:342-7; PMID:23184752; http://dx.doi.org/10.1002/adhm.201100047.
92. Xiang Y, Wu Q, Liang L, Wang X, Wang J, Zhang X, Pu X, Zhang Q. Chlorotoxin-modified stealth liposomes encapsulating levodopa for the targeting delivery against Parkinson’s disease in the MPTPinduced mice model. J Drug Target 2012; 20:67-75; PMID:22149216; http://dx.doi.org/10.3109/1061186X.2011.595490.
93. Huang R, Han L, Li J, Liu S, Shao K, Kuang Y, Hu X, Wang X, Lei H, Jiang C. Chlorotoxinmodified macromolecular contrast agent for MRI tumor diagnosis. Biomaterials 2011; 32:5177-86; PMID:21531455; http://dx.doi.org/10.1016/j.biomaterials.2011.03.075.
94. Xiang Y, Liang L, Wang X, Wang J, Zhang X, Zhang Q. Chloride channel-mediated brain glioma targeting of chlorotoxin-modified doxorubicine- loaded liposomes. J Control Release: Off J Control Release Soc 2011; 152:402-10; PMID:21435361; http://dx.doi.org/10.1016/j. jconrel.2011.03.014.
95. Fang C, Veiseh O, Kievit F, Bhattarai N, Wang F, Stephen Z, Li C, Lee D, Ellenbogen RG, Zhang M. Functionalization of iron oxide magnetic nanoparticles with targeting ligands: their physicochemical properties and in vivo behavior. Nanomedicine 2010; 5:1357-69; PMID:21128719; http://dx.doi.org/10.2217/nnm.10.55.
96. Lee MJ, Veiseh O, Bhattarai N, Sun C, Hansen SJ, Ditzler S, Knoblaugh S, Lee D, Ellenbogen R, Zhang M, et al. Rapid pharmacokinetic and biodistribution studies using cholorotoxin-conjugated iron oxide nanoparticles: a novel non-radioactive method. PLoS One 2010; 5:e9536; PMID: AMBIGUOUS
97. Meng XX, Wan JQ, Jing M, Zhao SG, Cai W, Liu EZ. Specific targeting of gliomas with multifunctional superparamagnetic iron oxide nanoparticle optical and magnetic resonance imaging contrast agents. Acta Pharmacol Sinic 2007; 28:2019-26; PMID:18031618; http://dx.doi.org/10.1111/j.1745-7254.2007.00661.x
98. Sun C, Du K, Fang C, Bhattarai N, Veiseh O, Kievit F, Stephen Z, Lee D, Ellenbogen RG, Ratner B, et al. PEG-mediated synthesis of highly dispersive multifunctional superparamagnetic nanoparticles: their physicochemical properties and function in vivo. ACS Nano 2010; 4:2402-10; PMID:20232826; http://dx.doi.org/10.1021/nn100190v
99. Sun C, Fang C, Stephen Z, Veiseh O, Hansen S, Lee D, Ellenbogen RG, Olson J, Zhang M. Tumor-targeted drug delivery and MRI contrast enhancement by chlorotoxin-conjugated iron oxide nanoparticles. Nanomedicine 2008; 3:495-505; PMID:18694312; http://dx.doi.org/10.2217/17435889.3.4.495.
100. Sun C, Veiseh O, Gunn J, Fang C, Hansen S, Lee D, Sze R, Ellenbogen RG, Olson J, Zhang M. In vivo MRI detection of gliomas by chlorotoxin-conjugated superparamagnetic nanoprobes. Small 2008; 4:372-9; PMID:18232053; http://dx.doi.org/10.1002/smll.200700784.
101. Veiseh O, Gunn JW, Kievit FM, Sun C, Fang C, Lee JS, Zhang M. Inhibition of tumor-cell invasion with chlorotoxin-bound superparamagnetic nanoparticles. Small 2009; 5:256-64; PMID:19089837; http://dx.doi.org/10.1002/smll.200800646.
102. Veiseh O, Sun C, Fang C, Bhattarai N, Gunn J, Kievit F, Du K, Pullar B, Lee D, Ellenbogen RG, et al. Specific targeting of brain tumors with an optical/magnetic resonance imaging nanoprobe across the blood-brain barrier. Cancer Res 2009; 69:6200-7; PMID:19638572; http://dx.doi.org/10.1158/0008-5472.CAN-09-1157.
103. Wan J, Meng X, Liu E, Chen K. Incorporation of magnetite nanoparticle clusters in fluorescent silica nanoparticles for high-performance brain tumor delineation. Nanotechnology 2010; 21:235104; PMID:20472942; http://dx.doi.org/10.1088/0957- 4484/21/23/235104.
104. Orndorff RL, Rosenthal SJ. Neurotoxin quantum dot conjugates detect endogenous targets expressed in live cancer cells. Nano Letters 2009; 9:2589-99; PMID:19507837; http://dx.doi.org/10.1021/nl900789e
105. Safdar S, Payne CA, Tu NH, Taite LJ. Targeted nitric oxide delivery preferentially induces glioma cell chemosensitivity via altered p53 and O(6) -methylguanine-DNA methyltransferase activity. Biotechnol Bioeng 2013; 110:1211-20; PMID: 23125026; http://dx.doi.org/10.1002/bit.24775.
106. Zhan C, Yan Z, Xie C, Lu W. Loop 2 ofOphiophagus hannah toxin b binds with neuronal nicotinic acetylcholine receptors and enhances intracranial drug delivery. Mol Pharm 2010; 7:1940-7; PMID: 20964364; http://dx.doi.org/10.1021/mp100238j
107. Maus L, Dick O, Bading H, Spatz JP, Fiammengo R. Conjugation of peptides to the passivation shell of gold nanoparticles for targeting of cell-surface receptors. ACS Nano 2010; 4:6617-28; PMID:20939520; http://dx.doi.org/10.1021/nn101867w
108. Francis JW, Figueiredo D, vanderSpek JC, Ayala LM, Kim YS, Remington MP, Young PJ, Lorson CL, Ikebe S, Fishman PS, et al. A survival motor neuron:tetanus toxin fragment C fusion protein for the targeted delivery of SMN protein to neurons. Brain Res 2004; 995:84-96; PMID:14644474; http://dx.doi.org/10.1016/j.brainres.2003.09.063.
109. Ciriza J, Moreno-Igoa M, Calvo AC, Yague G, Palacio J, Miana-Mena FJ, Munoz MJ, Zaragoza P, Brulet P, Osta R. A genetic fusion GDNF-C fragment of tetanus toxin prolongs survival in a symptomatic mouse ALS model. Restor Neurol Neurosci 2008; 26:459-65; PMID:19096133.
110. Chian RJ, Li J, Ay I, Celia SA, Kashi BB, Tamrazian E, Matthews JC, Bronson RT, Rossomando A, Pepinsky RB, et al. IGF-1:tetanus toxin fragment C fusion protein improves delivery of IGF-1 to spinal cord but fails to prolong survival of ALS mice. Brain Res 2009; 1287:1-19; PMID:19563785; http://dx.doi.org/10.1016/j.brainres.2009.06.066.
111. Figueiredo DM, Hallewell RA, Chen LL, Fairweather NF, Dougan G, Savitt JM, Parks DA, Fishman PS. Delivery of recombinant tetanussuperoxide dismutase proteins to central nervous system neurons by retrograde axonal transport. Exp Neurol 1997; 145:546-54; PMID:9217090; http://dx.doi.org/10.1006/exnr.1997.6490.
112. Favretto ME, Wallbrecher R, Schmidt S, van de Putte R, Brock R. Glycosaminoglycans in the cellular uptake of drug delivery vectors - Bystanders or active players? J Control Release: Off J Control Release Soc 2014; 180C:81-90; http://dx.doi.org/10.1016/j.jconrel.2014.02.011.
113. Ng CP, Goodman TT, Park IK, Pun SH. Biomimetic surface engineering of plasmid-loaded nanoparticles for active intracellular trafficking by actin comet-tail motility. Biomaterials 2009; 30:951-8; PMID:19046764; http://dx.doi.org/10.1016/j.biomaterials.2008.10.059.
114. Niu Y, Yu M, Hartono SB, Yang J, Xu H, Zhang H, Zhang J, Zou J, Dexter A, Gu W, et al. Nanoparticles mimicking viral surface topography for enhanced cellular delivery. Adv Mater 2013; 25:6233-7; PMID:23946251; http://dx.doi.org/10.1002/adma.201302737.
115. Srikanth M, Kessler JA. Nanotechnology-novel therapeutics for CNS disorders. Nat Rev Neurol 2012; 8:307-18; PMID:22526003; http://dx.doi.org/10.1038/nrneurol.2012.76.
116. Schneider-Schaulies J, Meulen V, Schneider-Schaulies S. Measles infection of the central nervous system. J Neurovirol 2003; 9:247-52; PMID:12707855; http://dx.doi.org/10.1080/13550280390193993.
117. Compton T. Receptors and immune sensors: the complex entry path of human cytomegalovirus. Trends Cell Biol 2004; 14:5-8.
118. Li Q, Ali MA, Cohen JI. Insulin degrading enzyme is a cellular receptor mediating varicella-zoster virus infection and cell-to-cell spread. Cell 2006; 127:305-16; PMID:17055432; http://dx.doi.org/10.1016/j.cell.2006.08.046.
119. Chen JJ, Zhu Z, Gershon AA, Gershon MD. Mannose 6-phosphate receptor dependence of varicella zoster virus infection in vitro and in the epidermis during varicella and zoster. Cell 2004; 119:915-26; PMID:15620351; http://dx.doi.org/10.1016/j.cell.2004.11.007.
120. Dunfee R, Thomas ER, Gorry PR, Wang J, Ancuta P, Gabuzda D. Mechanisms of HIV-1 neurotropism. Curr HIV Res 2006; 4:267-78; PMID:16842080; http://dx.doi.org/10.2174/157016206777709500.
121. Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med 2004; 10:1366-73; PMID:15558055; http://dx.doi.org/10.1038/nm1140.
122. Chu JJ, Ng ML. Interaction of West Nile virus with alpha v beta 3 integrinmediates virus entry into cells. J Biol Chem 2004; 279:54533-41; PMID:15475343; http://dx.doi.org/10.1074/jbc.M410208200.
123. Racaniello VR. One hundred years of poliovirus pathogenesis. Virology 2006; 344:9-16; PMID: AMBIGUOUS
124. Chung JW, Hong SJ, Kim KJ, Goti D, Stins MF, Shin S, Dawson VL, Dawson TM, Kim KS. 37- kDa laminin receptor precursor modulates cytotoxic necrotizing factor 1-mediated RhoA activation and bacterial uptake. J Biol Chem 2003; 278:16857-62; PMID:12615923; http://dx.doi.org/10.1074/jbc. M301028200.
125. Thepparit C, Smith DR. Serotype-specific entry of dengue virus into liver cells: identification of the 37- kilodalton/67-kilodalton high-affinity laminin receptor as a dengue virus serotype 1 receptor. J Virol 2004; 78:12647-56; PMID:15507651; http://dx.doi.org/10.1128/JVI.78.22.12647-12656. 2004.
126. Bogachek MV, Protopopova EV, Loktev VB, Zaitsev BN, Favre M, Sekatskii SK, Dietler G. Immunochemical and single molecule force spectroscopy studies of specific interaction between the laminin binding protein and the West Nile virus surface glycoprotein E domain II. J Mol Recognit 2008; 21:55-62; PMID:18061925; http://dx.doi.org/10.1002/jmr.866.
127. Protopopova EV, Sorokin AV, Konovalova SN, Kachko AV, Netesov SV, Loktev VB. Human laminin binding protein as a cell receptor for the tickborne encephalitis virus. Zbl Bakt 1999; 289:632-8; PMID:10215633.
128. Hurtado A, Tseng JC, Boivin C, Levin B, Yee H, Pampeno C, Meruelo D. Identification of amino acids of Sindbis virus E2 protein involved in targeting tumor metastases in vivo. Mol Ther: J Am Soc Gene Ther 2005; 12:813-23; PMID:16109508; http://dx.doi.org/10.1016/j.ymthe.2005.06.476.
129. Wang KS, Kuhn RJ, Strauss EG, Ou S, Strauss JH. High-affinity laminin receptor is a receptor for Sindbis virus in mammalian cells. J Virol 1992; 66:4992-5001; PMID:1385835.
130. Thongtan T, Wikan N, Wintachai P, Rattanarungsan C, Srisomsap C, Cheepsunthorn P, Smith DR. Characterization of putative Japanese encephalitis virus receptor molecules on microglial cells. J Med Virol 2012; 84:615-23; PMID:22337301; http://dx.doi.org/10.1002/jmv.23248.
131. Zhan C, Yan Z, Xie C, Lu W. Loop 2 ofOphiophagus hannah toxin b binds with neuronal nicotinic acetylcholine receptors and enhances intracranial drug delivery. Mol Pharm 2010; 7:1940-7; PMID:20964364; http://dx.doi.org/10.1021/mp100238j
132. Marcon F, Leblanc M, Vetter I, Lewis RJ, Escoubas P, Nicholson GM. Pharmacological characterization of alpha-elapitoxin-Al2a from the venom of the Australian pygmy copperhead (Austrelaps labialis): an atypical long-chain alpha-neurotoxin with only weak affinity for alpha7 nicotinic receptors. Biochem Pharmacol 2012; 84:851-63; PMID:22771828; http://dx.doi.org/10.1016/j. bcp.2012.06.024.
133. Kauferstein S, Kendel Y, Nicke A, Coronas F, Possani L, Favreau P, Krizaj I, Wunder C, Kauert G, Mebs D. New conopeptides of the D-superfamily selectively inhibiting neuronal nicotinic acetylcholine receptors. Toxicon: Off J Int Soc Toxinol 2009; 54:295-301; PMID:19393680; http://dx.doi.org/10.1016/j.toxicon.2009.04.016.
134. Whiteaker P, Christensen S, Yoshikami D, Dowell C, Watkins M, Gulyas J, Rivier J, Olivera BM, McIntosh JM. Discovery, synthesis, and structure activity of a highly selective a7 nicotinic acetylcholine receptor antagonist. Biochemistry 2007; 46:6628-38; PMID:17497892; http://dx.doi.org/10.1021/bi7004202.
135. Dutertre S, Ulens C, Büttner R, Fish A, van Elk R, Kendel Y, Hopping G, Alewood PF, Schroeder C, Nicke A. AChBP-targeted a-conotoxin correlates distinct binding orientations with nAChR subtype selectivity. EMBO J 2007; 26:3858-67; PMID: 17660751; http://dx.doi.org/10.1038/sj.emboj. 7601785.
136. Inserra MC, Kompella SN, Vetter I, Brust A, Daly NL, Cuny H, Craik DJ, Alewood PF, Adams DJ, Lewis RJ. Isolation and characterization of a-conotoxin LsIA with potent activity at nicotinic acetylcholine receptors. Biochem Pharmacol 2013; 86:791-9; PMID:23924607; http://dx.doi.org/10.1016/j.bcp.2013.07.016.
137. Yu R, Craik DJ, Kaas Q. Blockade of neuronal a7- nAChR by a-conotoxin ImI explained by computational scanning and energy calculations. PLoS Computat Biol 2011; 7:e1002011; PMID:AMBIGUOUS
138. Liu Y, Guo Y, An S, Kuang Y, He X, Ma H, Li J, Lv J, Zhang N, Jiang C. Targeting caspase-3 as dual therapeutic benefits by RNAi facilitating brain-targeted nanoparticles in a rat model of Parkinson’s disease. PloS One 2013; 8:e62905;
139. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011; 29:341-5; PMID:21423189; http://dx.doi.org/10.1038/nbt.1807.
140. Hwang do W, Son S, Jang J, Youn H, Lee S, Lee D, Lee YS, Jeong JM, Kim WJ, Lee DS. A brain-targeted rabies virus glycoprotein-disulfide linked PEI nanocarrier for delivery of neurogenic microRNA. Biomaterials 2011; 32:4968-75; PMID:21489620; http://dx.doi.org/10.1016/j. biomaterials.2011.03.047.
141. Fu A, Wang Y, Zhan L, Zhou R. Targeted delivery of proteins into the central nervous system mediated by rabies virus glycoprotein-derived peptide. Pharmaceut Res 2012; 29:1562-9; PMID:22231987; http://dx.doi.org/10.1007/s11095-012-0667-y
142. Kim JY, Choi WI, Kim YH, Tae G. Brain-targeted delivery of protein using chitosan- and RVG peptideconjugated, pluronic-based nano-carrier. Biomaterials 2013; 34:1170-8; PMID:23122677; http://dx.doi.org/10.1016/j.biomaterials.2012.09.047.
143. Chen W, Zhan C, Gu B, Meng Q, Wang H, Lu W, Hou H. Targeted brain delivery of itraconazole via RVG29 anchored nanoparticles. J Drug Target 2011; 19:228-34; PMID:20540685; http://dx.doi.org/10.3109/1061186X.2010.492523.
144. Liu Y, Huang R, Han L, Ke W, Shao K, Ye L, Lou J, Jiang C. Brain-targeting gene delivery and cellular internalization mechanisms for modified rabies virus glycoprotein RVG29 nanoparticles. Biomaterials 2009; 30:4195-202; PMID:19467700; http://dx.doi.org/10.1016/j.biomaterials.2009.02.051.
145. Andreu A, Fairweather N, Miller AD. Clostridium neurotoxin fragments as potential targeting moieties for liposomal gene delivery to the CNS. Chembiochem: Eur J Chem Biol 2008; 9:219-31; PMID:18076008; http://dx.doi.org/10.1002/cbic.200700277.
146. Knight A, Carvajal J, Schneider H, Coutelle C, Chamberlain S, Fairweather N. Non-viral neuronal gene delivery mediated by the HC fragment of tetanus toxin. Eur J Biochem/FEBS 1999; 259:762-9; PMID:10092862.
147. Moreno-Igoa M, Calvo AC, Ciriza J, Munoz MJ, Zaragoza P, Osta R. Non-viral gene delivery of the GDNF, either alone or fused to the C-fragment of tetanus toxin protein, prolongs survival in a mouse ALS model. Restor Neurol Neurosci 2012; 30: 69-80; PMID:22124037.
148. Oliveira H, Fernandez R, Pires LR, Martins MC, Simoes S, Barbosa MA, Pego AP. Targeted gene delivery into peripheral sensorial neurons mediated by self-assembled vectors composed of poly(ethylene imine) and tetanus toxin fragment c. J Control Release: Off J Control Release Soc 2010; 143:350-8; PMID:20093157; http://dx.doi.org/10.1016/j. jconrel.2010.01.018.
149. Benn SC, Ay I, Bastia E, Chian RJ, Celia SA, Pepinsky RB, Fishman PS, Brown RH, Jr., Francis JW. Tetanus toxin fragment C fusion facilitates protein delivery to CNS neurons from cerebrospinal fluid inmice. JNeurochem 2005; 95:1118-31; PMID:16271047; http://dx.doi.org/10.1111/j.1471-4159.2005.03459.x
150. Carlton E, Teng Q, Federici T, Yang J, Riley J, Boulis NM. Fusion of the tetanus toxin C fragment binding domain and Bcl-xL for protection of peripheral nerve neurons. Neurosurgery 2008; 63:1175-82; http://dx.doi.org/10.1227/01.NEU.0000334415.45003.EA
151. Francis JW, Hosler BA, Brown RH, Jr., Fishman PS. CuZn superoxide dismutase (SOD-1):tetanus toxin fragment C hybrid protein for targeted delivery of SOD-1 to neuronal cells. J Biol Chem 1995; 270:15434-42; PMID:7797532; http://dx.doi.org/10.1074/jbc.270.25.15434.
152. Gramlich PA, Remington MP, Amin J, Betenbaugh MJ, Fishman PS. Tat-tetanus toxin fragment C: a novel protein delivery vector and its use with photochemical internalization. J Drug Target 2013; 21:662-74; PMID:23697582; http://dx.doi.org/10.3109/1061186X.2013.796954.
153. Larsen KE, Benn SC, Ay I, Chian RJ, Celia SA, Remington MP, Bejarano M, Liu M, Ross J, Carmillo P, et al. A glial cell line-derived neurotrophic factor (GDNF): tetanus toxin fragment C protein conjugate improves delivery of GDNF to spinal cord motor neurons in mice. Brain Res 2006; 1120:1-12; PMID:17020749; http://dx.doi.org/10.1016/j.brainres.2006.08.079.
154. Li J, Chian RJ, Ay I, Kashi BB, Celia SA, Tamrazian E, Pepinsky RB, Fishman PS, Brown RH, Jr., Francis JW. Insect GDNF:TTC fusion protein improves delivery of GDNF to mouse CNS. Biochem Biophys Res Commun 2009; 390:947-51; PMID:19852934; http://dx.doi.org/10.1016/j.bbrc.2009.10.083.
155. Townsend SA, Evrony GD, Gu FX, Schulz MP, Brown RH, Jr., Langer R. Tetanus toxin C fragment- conjugated nanoparticles for targeted drug delivery to neurons. Biomaterials 2007; 28:5176-84; PMID:17854886; http://dx.doi.org/10.1016/j. biomaterials.2007.08.011